Colorectal cancer (CRC) is third leading cause of the morbidity and mortality for both men and women in well-developed and industrialized countries like United States and United Kingdom. (Ponz de Leon M, Percesepe A. Pathogenesis of colorectal cancer. Digestive and Liver Disease 2000; 32:807-21). In the United States alone, it is the third most common neoplasm incurring health care costs estimated at $8 billion. Approximately 75% of CRCs are sporadic and occur in average-risk individuals without a familial predisposition.
Colon cancer arises from the pre-existing adenomatous polyps which are dysplastic or neoplastic lesions at an early stage. Colon cancer is treatable is detected early and survival is improved by early diagnosis. Hence, screening for CRC is recommended for persons≧50 years of age. Patients diagnosed with advanced CRC typically die within 5 years. Without screening, CRC is typically detected as adenocarcinoma at an advanced stage, where treatments are less effective.
Currently available screening techniques include: (1) fecal occult blood testing (FOBT) which detects only 30-40% of CRC and 10% of adenomas; (2) sigmoidoscopy fails to detect lesions in the proximal colon which represents 40% of all colorectal cancers, misses 10-15% of sigmoid colon carcinomas, and is uncomfortable for patients; (3) double contrast barium enema (DCBE), which visualizes the entire colon but has only 44% sensitivity for detection of polyps >1 cm in diameter, is highly operator-dependent, and is uncomfortable for the patient; and (4) colonoscopy which is the current standard of care, but has a significant miss rate of 24% for adenomas overall, 27% of adenomas <5 mm, 13% of adenomas 6-9 mm, and 6% of adenomas >1 cm. Colonoscopy also fails to reach the caecum of 5-10% of average risk patients. (Fenlon H M. Virtual colonoscopy. The British journal of surgery 2002; 89:1-3). Failure rates for colonoscopy, barium enema and flexible sigmoidoscopy are 9%, 20% and 50% respectively. (Frenette C, Strum W. Relative Rates of Missed Diagnosis for Colonoscopy, Barium Enema, and Flexible Sigmoidoscopy in 379 Patients with Colorectal Cancer. Journal of Gastrointestinal Cancer 2007; 38:148-53). Possibly of greater importance, colonoscopy has a problem of low patient compliance, which may be due the requirement of a cathartic bowel preparation, general anesthesia, cost and the invasiveness of the procedure.
In addition to colonoscopy, an emerging, less invasive method is Virtual Colonoscopy (VC) wherein multi-slice computed tomography (CT-VC) and magnetic resonance imaging (MRI-VC) images are analyzed for the presence of visible (>0.5 cm) polyps. Although VC methods require bowel preparation and distention of the bowel by insufflation of the bowel, these image acquisitions are short in duration relative to the length of the colonoscopy procedure and do not require anesthesia thus VC procedures tend to be lower in cost. The entire colon is visualized, allowing for accurate and sensitive lesion detection. However, specificity of detection for these methods is lower than colonoscopy. As with colonoscopy, an inadequate bowel preparation can lead to false positives. Hence, currently available screening methods for CRC suffer from low patient compliance, high cost and inadequate specificity and sensitivity of detection due to the colon's complicated physiology and inadequate bowel preparation. (Edwards C. Physiology of the colorectal barrier. Advanced Drug Delivery Reviews 1997; 28:173-90)
The genetic model of colorectal carcinogenesis developed by Vogelstein et al. has shown that there is an accumulation of a series of molecular genetic abnormalities over time that determines the neoplastic phenotype of CRC. (Fearon E R, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759-67; Finlay G J. Genetics, molecular biology and colorectal cancer. Mutation research 1993; 290:3-12). In the last 2-3 decades, we have greatly improved our understanding of tumor biology, molecular pathways, and the hereditary and environmental factors that lead to colon carcinogenesis. Based on the molecular profile of colon tumors, there is an opportunity to develop targeted diagnostic methods with potential for use in personalized patient care. (Neal C P, Garcea G, Doucas H, Manson M M, Sutton C D, Dennison A R, et al. Molecular prognostic markers in resectable colorectal liver metastases: a systematic review. Eur J Cancer 2006; 42:1728-43; Bosman F T. Prognostic value of pathological characteristics of colorectal cancer. Eur J Cancer 1995; 31A:1216-21). The discovery of molecular markers that are expressed on the tumor cell-surface may lead to the development of targeted molecular imaging and therapeutic agents for CRC.
For the early detection and prognostic prediction of colon cancer, the screening methods available have not that specificity and sensitivity because of colon's complicated physiology and cleaning process. (Edwards C. Physiology of the colorectal barrier. Advanced Drug Delivery Reviews 1997; 28:173-90). For this reason, what is needed is an alternative screening/detection approach that is able to reliably and accurately detect colon cancer in its earliest stages.